The present invention relates to the treatment of multidrug resistance in certain parasitic diseases. In addition to having been observed in malaria, multidrug resistance is a phenomenon which has been observed in other parasitic diseases such as Entamoeba histolytica (amoebic dysentery), Trypanosoma (African sleeping sickness), Leishmania and AIDS pneumonia.
A number of diverse drugs have been found effective against such diseases. However in many cases, the initial success of physicians in treating the disease is followed by total failure. Drugs which worked initially become totally ineffective after a period of time. An initial period of remission is often followed by a period of frustration during which nothing seems to be effective against the disease. Death becomes inevitable.
Such multidrug resistance in cancer cells has been associated with an increase in the drug resistant cell in the presence of 150,000 to 170,000 molecular weight glycoproteins in the drug resistant cell. Such P150-170 Kd glycoproteins act as a drug exit pump, to pump disease fighting drugs out of the infected or infecting cells which the drugs are supposed to kill. This glycoprotein pump phenomenon in cancer cells has been reported in a March 1989 Scientific American article by Kartner and Ling. (No concession is made that this publication is prior art as to subject matter contained in the parent applications.) The presence of a very similar glycoprotein pump in drug resistant malaria has also been discovered by the inventor.
It has been reported by Rothenberg and Ling that multidrug resistance in cancer can be reversed by using hydrophobic molecules with two planar aromatic rings and a tertiary basic nitrogen atom with a positive charge at physiologic pH. Journal of the National Cancer Institute, Vol. 81, No. 12, Jun. 21, 1989, on page 907. (No concession is made that this publication is prior art.) A representative compound of this class, and indeed apparently a major member of this class which has actually been the subject of experimental work is the drug verapamil, whose structural formula is shown below: ##STR1##
Verapamil is a calcium channel blocker. Other researchers have claimed that calcium channel blockers are effective against malaria. However while such results may be substantiatable in vitro, they have little practical value as clinical treatments in vivo. While calcium channel blockers are therapeutic in the treatment of hypertension at moderate levels, they are toxic at levels high enough to effect MDR reversal.
Another technique for MDR reversal in cancer which is of laboratory interest but which has no practical applicability involves inducing point mutations of the energy related ATP binding sites in the glycoprotein. Such point mutations result in an almost complete loss of MDR activity, according to Rothenberg and Ling, supra. While such in vitro work is important, it lacks in vivo clinical applicability.
Shiraishi et al. disclose work on the use of cepharanthine to treat multidrug resistance in cancer. Isotetrandrine, tetrandrine, fangchinoline and herbamine are said to show similar effects in cancer. Anti-tumor effects of tetrandrine have also been mentioned.
Researchers throughout the world continue to press for techniques for reversing multidrug resistance. A successful clinical technique for reversing multidrug resistance will be one of the most important breakthroughs in the fight against parasitic diseases exhibiting the multidrug resistance phenomenon.